PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of bmjclinevidLink to Publisher's site
 
BMJ Clin Evid. 2008; 2008: 0404.
Published online 2008 September 3.
PMCID: PMC2907976

Stomach cancer

Charles Bailey, MRCS, Surgical Specialist Registrar

Abstract

Introduction

Stomach cancer is usually an adenocarcinoma arising in the stomach, and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). The annual incidence varies among countries and by sex, with about 80 cases a year per 100,000 in Japanese men, 30/100,000 in Japanese women, 18/100,000 in British men, and 10/100,000 in British women.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of radical versus conservative surgical resection? What are the effects of adjuvant chemotherapy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: adjuvant chemoradiotherapy, adjuvant chemotherapy, lymphadenectomy (radical, conservative), removal of adjacent organs, and subtotal gastrectomy for resectable distal tumours.

Key Points

Stomach cancer is usually an adenocarcinoma arising in the stomach and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). Only non-metastatic stomach cancers are considered in this review.

  • The incidence varies among countries and by gender, with about 80 cases a year per 100,000 in Japanese men, 30/100,000 in Japanese women, 18/100,000 in British men, and 10/100,000 in British women.

With regard to surgical resection, subtotal gastrectomy seems as effective as total gastrectomy.

  • In practice, surgeons sometimes recommend total gastrectomy "de principe" in people with poorly differentiated "diffuse" cancer, to prevent infiltration of microscopic tumour deposits into the proximal resection margin.

Removal of adjacent organs (spleen and distal pancreas) is associated with increased morbidity and mortality compared with gastrectomy alone.

  • Current consensus is that adjacent organs should only be removed to ensure complete tumour removal, or when required because of trauma during surgery.

We found insufficient evidence to judge the effectiveness of radical lymphadenectomy compared with conservative lymphadenectomy.

Adjuvant chemoradiotherapy seems to improve survival compared with surgery alone in people with resectable stomach adenocarcinoma.

Adjuvant chemotherapy might also be effective compared with surgery alone, although the evidence is inconsistent.

About this condition

Definition

Stomach cancer is usually an adenocarcinoma arising in the stomach, and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). Tumours are staged according to degree of invasion and spread (see table 1 ). Only non-metastatic stomach cancers are considered in this review.

Table 1
Staging of stomach cancer (see text).

Incidence/ Prevalence

The incidence of stomach cancer varies among countries and by sex (incidence per 100,000 population a year in Japanese men is about 80, Japanese women 30, British men 18, British women 10, white American men 11, and white American women 7). Incidence has declined dramatically in North America, Australia, and New Zealand since 1930, but the decline in Europe has been slower. In the USA, stomach cancer remains relatively common among particular ethnic groups, especially Japanese-Americans, and some Hispanic groups. The incidence of cancer of the proximal stomach and gastro-oesophageal junction is rising rapidly in many European populations and in North America. The reasons for this are poorly understood.

Aetiology/ Risk factors

Distal stomach cancer is strongly associated with lifelong infection with Helicobacter pylori and poor dietary intake of antioxidant vitamins (A, C, and E). In Western Europe and North America, distal stomach cancer is associated with relative socioeconomic deprivation. Proximal stomach cancer is strongly associated with smoking (OR about 4), and is probably associated with gastro-oesophageal reflux, obesity, high fat intake, and medium to high socioeconomic status.

Prognosis

Invasive stomach cancer (stages T2-T4) is fatal without surgery. Mean survival without treatment is less than 6 months from diagnosis. Intramucosal or submucosal cancer (stage T1) may progress slowly to invasive cancer over several years. In the USA, over 50% of people recently diagnosed with stomach cancer have regional lymph node metastasis or involvement of adjacent organs. The prognosis after macroscopically and microscopically complete resection (R0) is related strongly to disease stage, particularly penetration of the serosa (stage T3) and lymph node involvement. Five-year survival rates range from over 90% in intramucosal cancer to about 20% in people with stage T3N2 disease (see table 1 ). In Japan, the 5-year survival rate for people with advanced disease is reported to be about 50%, but the explanation for the difference remains unclear. Comparisons between Japanese and Western practice are confounded by factors such as age, fitness, and disease stage, as well as by tumour location, because many Western series include gastro-oesophageal junction adenocarcinoma, which is associated with a much lower survival rate after surgery.

Aims of intervention

To prevent progression; extend survival; and relieve symptoms, with minimal adverse effects.

Outcomes

Survival; quality of life; adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal August 2007. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE clinical guidelines. The author also performed hand searches of conference proceedings and consultations with experts to identify relevant studies in August 2004. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. In many instances, we have separated trials and results from different geographical areas, because of differences in baseline risk and demographics and possible differences in responses to treatments. However, the meanings of terms to describe such populations, such as "Western" and "Asian" were not clearly defined in many identified studies. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for stomach cancer

Glossary

Adjuvant chemotherapy
Treatment with cytotoxic drugs given in addition to surgery in an attempt to achieve cure.
Conservative lymphadenectomy (D1)
Removal of perigastric lymph nodes — lymph nodes that lie adjacent to the stomach.
Disease stage
Surgical and microscopic assessment of the primary tumour. Microscopic spread to distant sites can be detected only by radical surgery, creating a potential bias.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Radical lymphadenectomy (D2)
Removal of regional lymph nodes — lymph nodes that lie along the blood vessels that supply the stomach.
Stage migration bias
Apparent increase in stage-specific survival without influencing overall survival caused by recategorisation of the stage after removal of diseased lymph nodes.
Subtotal distal gastrectomy
Removal of the lower part (usually two thirds or four fifths) of the stomach.
Total gastrectomy
Removal of the whole stomach.
Total gastrectomy “de principe”
Total gastrectomy where it is not technically necessary (i.e. for a distal cancer which could be removed using a partial gastrectomy).

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

References

1. Whelan SL, Parkin DM, Masuyer E, eds. Trends in cancer incidence and mortality (IARC scientific publication no. 102). Lyon: IARC Scientific Publications, 1993.
2. Cancer Research Campaign. Factsheet 18. London: Cancer Research Campaign, 1993.
3. Powell J, McConkey CC. Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. Br J Cancer 1990;62:440–443. [PMC free article] [PubMed]
4. Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049–2053. [PubMed]
5. EUROGAST study group. An international association between Helicobacter pylori infection and gastric cancer. Lancet 1993;341:1359–1362. [PubMed]
6. Buiatti E, Palli D, Decarli A, et al. A case-control study of gastric cancer and diet in Italy. II Association with nutrients. Int J Cancer 1990;45:896–901. [PubMed]
7. Rios-Castellanos E, Sitas F, Shepherd NA, et al. Changing pattern of gastric cancer in Oxfordshire. Gut 1992;33:1312–1317. [PMC free article] [PubMed]
8. Boddie AW Jr, McMurtrey MJ, Giacco GG, et al. Palliative total gastrectomy and esophagogastrectomy: an evaluation. Cancer 1983;51:1195–2000. [PubMed]
9. McCulloch P. Should general surgeons treat gastric carcinoma? An audit of practice and results. Br J Surg 1994;81:417–420. [PubMed]
10. Kohli Y, Kawai K, Fujita S. Analytical studies of the growth of human gastric cancer. J Clin Gastroenterol 1981;3:129–133. [PubMed]
11. Bozzetti F, Marubini E, Bonfanti G, et al. Total versus subtotal gastrectomy: surgical morbidity and mortality rates in a multicenter Italian randomized trial. Ann Surg 1997;226:613–620. [PubMed]
12. Bozzetti F, Marubini E, Bonfanti G, et al. Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Ann Surg 1999;230:170–178. [PubMed]
13. Gouzi JL, Huguier M, Fagniez PL, et al. Total gastrectomy versus partial gastrectomy of adenocarcinoma of the antrum. A French prospective controlled study. Ann Chir 1989;43:356–360. [In French] [PubMed]
14. Gouzi JL, Huguier M, Fagniez PL, et al. Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg 1989;209:162–166. [PubMed]
15. McCulloch P, Nita ME, Kazi H, et al. Extended versus limited lymph nodes dissection technique for adenocarcinoma of the stomach. In: The Cochrane Library, Issue 3, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003; primary sources Medline, Embase, Cancerlit, Lilacs, Central Medical Journal Japanese Database and the Cochrane Register, hand searches of references from relevant articles and conference proceedings, and contact with researchers in the field.
16. Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 2004;22:2069–2077. [PubMed]
17. Parikh D, Chagla L, Johnson M, et al. D2 gastrectomy: lessons from a prospective audit of the learning curve. Br J Surg 1996;83:1595–1599. [PubMed]
18. Bunt AMG, Hermans J, Boon MC, et al. Evaluation of the extent of lymphadenectomy in a randomised trial of Western versus Japanese style surgery in gastric cancer. J Clin Oncol 1994;12:417–422. [PubMed]
19. Cuschieri A, Weedon S, Fielding J, et al. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomised surgical trial. Br J Cancer 1999;79:1522–1530. [PMC free article] [PubMed]
20. Siewert JR, Bottcher K, Stein HJ, et al. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228:449–461. [PubMed]
21. Csendes A, Burdiles P, Rojas J, et al. A prospective randomised study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma. Surgery 2002;131:401–407. [PubMed]
22. Yu W, Choi GS, Chung HY. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br J Surg 2006;93:559–563. [PubMed]
23. Bonenkamp JJ, Songun I, Hermans J, et al. Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 1995;345:745–748. [PubMed]
24. Cuschieri A, Fayers P, Fielding J, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. Lancet 1996;347:995–999. [PubMed]
25. Sano T, Yamanoto S, Sasako M. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric cancer. Jpn J Clin Oncol 2002;32:363–364. [PubMed]
26. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–730 [PubMed]
27. Mari E, Floriani I, Tinazzi A, et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente). Ann Oncol 2000;11:837–843. Search date 2000; primary sources Medline, Embase, Cancerlit, and hand searches of references. [PubMed]
28. Oba K, Morita S, Tsuburaya A, et al. Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: A meta-analysis of centrally randomized controlled clinical trials in Japan. J Chemother 2006;18:311–318. [PubMed]
29. Neri B, Cini G, Andreoli F, et al. Randomized trial of adjuvant chemotherapy versus control after curative resection for gastric cancer: 5-year follow-up. Br J Cancer 2001;84:878–880. [PMC free article] [PubMed]
30. Bajetta E, Buzzoni R, Mariani L, et al. Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group. Ann Oncol 2002;13:299–307. [PubMed]
31. Yonemura Y, De Aretxabala X, Fujimura T, et al. Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study. Hepato-gastroenterology 2001;48:1776–1782. [PubMed]
32. Chipponi J, Huguier M, Pezet D, et al. Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer. Am J Surg 2004;187:440–445. [PubMed]
33. Cunningham D, Allum WH, Stenning SP, et al. A perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New Engl J Med 2006;355:11–20. [PubMed]
34. Tentes AA, Markakidis SK, Karanikiotis C, et al. Intraarterial chemotherapy as an adjuvant treatment in locally advanced gastric cancer. Langenbeck's Arch Chir/Deutsche Gesellschaft für Chirurgie. 2006;391:124–129. [PubMed]
35. Coombes RC, Schein PS, Chilvers CE, et al. A randomised trial comparing adjuvant 5-fluoro-uracil, doxorubicin and mitomycin C with no treatment in operable gastric cancer. International Collaborative Cancer Group. J Clin Oncol 1990;8:1362–1369. [PubMed]
36. Hallissey MT, Dunn JA, Ward LC, et al. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in advanced gastric cancer: 5 year follow-up. Lancet 1994;343:1309–1312. [PubMed]
37. Alcobendas F, Milla A, Estape J, et al. Mitomycin C as an adjuvant in resected gastric cancer. Ann Surg 1983;198:13–17. [PubMed]
38. Grau JJ, Estape J, Alcobendas F. Positive results of adjuvant mitomycin C in resected gastric cancer: a randomised trial on 134 patients. Eur J Cancer 1993;29A:340–342. [PubMed]
2008; 2008: 0404.
Published online 2008 September 3.

Subtotal versus total gastrectomy for resectable distal tumours

Summary

MORTALITY Subtotal compared with total gastrectomy: We don't know whether subtotal gastrectomy is more effective at increasing survival at 5 years in people with primary tumours in the distal stomach ( moderate-quality evidence ).

Benefits

Five-year survival:

We found no systematic review but found two RCTs (787 people, 4 publications) comparing total versus subtotal gastrectomy. Neither RCT used blinded allocation. The first RCT (648 people aged less than 76 years with a resectable tumour and a macroscopic proximal margin of more than 6 cm) compared total versus subtotal gastrectomy. All people involved in the RCT had a regional lymphadenectomy (D2; see table 2 ) The RCT found no significant difference between total and subtotal gastrectomy in the incidence of microscopic resection margin involvement (15/315 [5%] with subtotal gastrectomy v 6/303 [2%] with total gastrectomy; ARI +2.8%, 95% CI –0.1% to +9.6%) or in 5-year survival (Kaplan–Meier 5-year survival estimates: 65% with subtotal gastrectomy v 62% with total gastrectomy; HR 0.89, 95% CI 0.68 to 1.17). Multivariate analysis found that, after adjustment for covariates, the type of stomach surgery had no significant effect on 5-year survival (HR 1.01, 95% CI 0.76 to 1.33). The second RCT (169 people with potentially curable distal stomach cancer) compared total versus subtotal gastrectomy, and found no significant difference in 5-year survival (48% in each group; CI not reported).

Table 2
Different types of surgical resection for stomach cancer (see text).

Quality of life:

We found no RCTs that examined quality of life with total compared with subtotal gastrectomy in people with resectable distal tumours.

Harms

Postoperative morbidity:

Morbidity included intra-abdominal sepsis, chest infections, wound sepsis, and fistulae. The first RCT found no significant difference between subtotal and total gastrectomy in postoperative morbidity (29/320 [9%] with subtotal gastrectomy v 40/304 [13%] with total gastrectomy; RR 0.67, 95% CI 0.44 to 1.08), although length of hospital stay was significantly longer in the total gastrectomy group (13.8 days with subtotal gastrectomy v 15.4 days with total gastrectomy, P less than 0.001). The second RCT also found no significant difference in postoperative morbidity (32/93 [34%] with subtotal gastrectomy v 25/76 [32%] with total gastrectomy; RR 1.05, 95% CI 0.68 to 1.60).

Postoperative mortality:

The first RCT found no significant difference in postoperative mortality (4/320 [1%] with subtotal gastrectomy v 7/304 [2%] with total gastrectomy; RR 0.54, 95% CI 0.16 to 1.84). The second RCT also found no significant difference in postoperative mortality (3/93 [3%] with subtotal gastrectomy v 1/76 [1%] with total gastrectomy; RR 2.45, 95% CI 0.26 to 23.01).

Comment

Clinical guide:

Infiltration of the proximal resection margin by microscopic tumour deposits is perceived as a problem in people with poorly differentiated “diffuse” cancer of the distal stomach having distal subtotal gastrectomy. Some surgeons have therefore recommended total gastrectomy “de principe” for these tumours. The two RCTs found similar survival after total and subtotal gastrectomy in people with primary tumours in the distal stomach. Both RCTs recruited otherwise-fit people, which may explain the low postoperative mortality.

Substantive changes

No new evidence

2008; 2008: 0404.
Published online 2008 September 3.

Radical versus conservative lymphadenectomy

Summary

MORTALITY Radical compared with conservative lymphadenectomy: We don't know whether radical lymphadenectomy is more effective at increasing survival at 5 or 10 years ( low-quality evidence ).

Benefits

We found one systematic review (search date 2003, 2 RCTs, 1111 people), which found no significant difference in 5-year survival between radical and conservative lymphadenectomy (AR: 237/580 [41%] with conservative lymphadenectomy v 226/531 [43%] with radical lymphadenectomy; RR 0.95, 95% CI 0.83 to 1.09). Ten-year follow-up of one of the RCTs included in the review found similar results (AR for survival: 30% with conservative lymphadenectomy v 35% with radical lymphadenectomy; P = 0.53).

Harms

The systematic review found that radical lymphadenectomy significantly increased postoperative mortality compared with conservative lymphadenectomy (AR: 28/572 [5%] with conservative lymphadenectomy v 58/523 [11%] with radical lymphadenectomy; RR 2.23, 95% CI 1.45 to 3.46). The excess postoperative mortality may have been due to pancreatic and splenic removal associated with radical lymphadenectomy. The 10-year follow-up of one of the RCTs included in the review did not report on harms; they were described in the original trial publication.

Comment

The RCTs were conducted by surgeons with limited prior experience and training in radical lymphadenectomy (D2 resection), and results may have been affected by both learning-curve effects, and failure to apply the assigned treatment (contamination and non-compliance). Subgroup analysis from one of the RCTs included in the review found a possible advantage for D2 resection in people with stage II and IIIA disease (corresponding to T1N2M0, T2N1M0, T3N0M0, T2N2M0, T3N1M0, and T4N0M0), particularly in those people who did not have additional organ removal. One large prospective cohort study (1654 people with gastric cancer) found no benefit from D2 resection (defined within this study as more than 25 lymph nodes removed; 300 people) compared with D1 resection (up to 25 nodes removed; 1096 people) in the entire cohort of people with gastric cancer after 10 years' follow-up. Subgroup analysis found that there may be a beneficial effect of D2 compared with D1 resection in the subgroup of people with stage II tumours (230 people; RR of long-term survival 1.8, 95% CI 1.3 to 2.7). Cohort studies comparing radical versus conservative lymphadenectomy are affected by numerous biases: selection bias (where surgeons reserve D2 surgery for younger or fitter people, or where recent D2 operations are compared with historical D1 controls); differing definitions of “limited” and “extended”; and stage migration bias. These biases make the interpretation of observational data difficult.

Substantive changes

No new evidence

2008; 2008: 0404.
Published online 2008 September 3.

Removal of adjacent organs

Summary

MORTALITY Total gastrectomy plus splenectomy compared with total gastrectomy: Total gastrectomy plus splenectomy and total gastrectomy alone are equally effective at increasing survival at 5 years ( moderate-quality evidence ). NOTE There is consensus that removal of adjacent organs is justified to ensure complete tumour removal, or when required because of trauma during surgery.

Benefits

We found no systematic review but found two RCTs. The first RCT (187 people aged 25–80 years) found no significant difference in 5-year survival rates for total gastrectomy plus splenectomy compared with total gastrectomy alone (42% with total gastrectomy plus splenectomy v 36% with total gastrectomy alone; P greater than 0.5; absolute numbers not reported). The second RCT (216 people, aged 24–78 years) compared total gastrectomy plus splenectomy versus total gastrectomy alone. It also found no significant difference in 5-year survival between the two groups (54.8% with total gastrectomy plus splenectomy v 48.8% with total gastrectomy alone; P = 0.503; absolute numbers not reported).

Harms

The first RCT (187 people) found that total gastrectomy plus splenectomy significantly increased the number of postoperative infections compared with total gastrectomy alone (fever above 38 °C, P less than 0.04; pulmonary infections, P less than 0.008; subphrenic abscesses, P less than 0.05), but found no significant difference in postoperative mortality (4/90 [4%] with total gastrectomy plus splenectomy v 3/97 [3%] with total gastrectomy alone; RR 1.40, 95% CI 0.33 to 6.24). The second RCT showed no significant difference in postoperative complications (15.4% with total gastrectomy plus splenectomy v 8.7% with total gastrectomy alone; P = 0.142). Retrospective analyses of RCTs and cohort studies, in which removal of the spleen and distal pancreas had been carried out routinely during radical total gastrectomy (D2) (see table 2 ), and at the surgeon's discretion during non-radical total gastrectomy (D1), found that removal of the spleen or distal pancreas was associated with increased perioperative mortality (OR about 2), and found no evidence of improved long-term survival.

Comment

Clinical guide:

Some advocates of radical surgery have suggested routine removal of the spleen and distal pancreas to ensure complete regional lymph node dissection during total gastrectomy. Current consensus is that removal of adjacent organs is justified only when necessary to ensure complete tumour removal, or when required because of trauma during surgery. One RCT has begun in Japan to evaluate the role of splenectomy in total gastrectomy for proximal gastric cancer.

Substantive changes

No new evidence

2008; 2008: 0404.
Published online 2008 September 3.

Adjuvant chemoradiotherapy

Summary

MORTALITY Compared with surgery: Adjuvant chemoradiotherapy seems more effective at increasing survival in people with resectable stomach adenocarcinoma ( moderate-quality evidence ).

Benefits

We found no systematic review, but found one RCT comparing adjuvant chemoradiotherapy versus surgery alone for resectable stomach adenocarcinoma. It found that adjuvant chemoradiotherapy significantly increased survival compared with surgery alone (556 people; median survival: 36 months with surgery plus chemoradiotherapy v 27 months with surgery alone; HR 1.35, 95% CI 1.09 to 1.66).

Harms

The RCT reported three treatment-related deaths in the adjuvant chemoradiotherapy group (3/273 [1%]). Grade 3 toxic effects occurred in 41% of people receiving chemoradiotherapy and grade 4 toxic effects in 32%. The RCT gave no information on harms in the surgery alone group.

Comment

Concerns have been raised about the lack of standardisation of the surgical resection technique. As surgery was not standardised, it is possible that resection was not thorough enough in some people, leaving them with residual disease — so that they may have benefited from chemoradiotherapy compared with no treatment. If the surgery had been thorough (i.e. standardised), adjuvant chemoradiotherapy may not have been found to be beneficial compared with no treatment.

Substantive changes

No new evidence

2008; 2008: 0404.
Published online 2008 September 3.

Adjuvant chemotherapy

Summary

MORTALITY Compared with surgery: Adjuvant chemotherapy seems more effective at improving overall survival in people with gastric adenocarcinoma, but may be poorly tolerated ( moderate-quality evidence ).

Benefits

Adjuvant chemotherapy versus surgery alone:

We found two systematic reviews and six subsequent RCTs, comparing adjuvant chemotherapy versus surgery alone. The first review (search date 2000, 20 RCTs, 3658 people; see comment below) found that adjuvant chemotherapy significantly reduced mortality compared with surgery alone (HR 0.82, 95% CI 0.75 to 0.89). The second review (search date 2005, 4 RCTs, 1330 people) was confined to trials performed in Japan (none of which were included in the first review), and also found that adjuvant chemotherapy significantly reduced mortality compared with surgery alone (HR 0.73, 95% CI 0.60 to 0.89, no absolute data reported). The first subsequent RCT (137 people with gastric adenocarcinoma and positive lymph nodes) compared adjuvant chemotherapy versus surgery alone, and found that adjuvant chemotherapy significantly increased median survival time (31 months [range 7 months to greater than 60 months] with adjuvant chemotherapy v 18 months [range 2 months to greater than 60 months] with surgery alone; P less than 0.01; HR for death 1.96, 95% CI 1.32 to 2.92). The second subsequent RCT (274 people with gastric adenocarcinoma T3, T4 or N1, N2) found no significant difference in 5-year survival between adjuvant chemotherapy and surgery alone (overall survival: 52% with adjuvant chemotherapy v 48% with surgery alone; HR 0.93, 95% CI 0.65 to 1.34). The third subsequent RCT (139 people) compared three groups: surgery plus hyperthermic intraperitoneal chemotherapy; surgery plus normothermic intraperitoneal chemotherapy; and surgery alone. It found that surgery plus hyperthermic chemotherapy (mitomycin C plus cisplatin at 42 °C) significantly increased overall 5-year survival rates compared with surgery alone (P = 0.01), and that surgery plus hyperthermic chemotherapy also significantly increased overall 5-year survival rates compared with surgery plus normothermic chemotherapy (mitomycin C plus cisplatin at 37 °C) (P = 0.05; absolute results presented graphically). Subgroup analysis found that these results were consistent for people with advanced disease (T3 or node positive), but, in people with less-advanced disease (T2 or node negative), subgroup analysis found no significant difference in overall 5-year survival rates. The fourth subsequent RCT (205 people with serosa- or lymph node-positive gastric cancer) also found no significant difference in 5-year survival between adjuvant chemotherapy and surgery alone (39% with adjuvant chemotherapy v 39% with surgery alone). However, owing to treatment-related toxicity, 54% of people did not complete the course of chemotherapy, and 32% completed chemotherapy at a decreased dose. The fifth subsequent RCT of gastro-oesophageal cancer (including cancers of the stomach [372 people], gastro-oesophageal junction [58 people], and lower third of the oesophagus [73 people]) compared perioperative chemotherapy plus surgery versus surgery alone. It found significantly improved rates of progression-free and overall survival for perioperative chemotherapy compared with surgery alone at a median follow-up of 4 years (progression-free survival: HR 0.66, 95% CI 0.53 to 0.81, P less than 0.001; overall survival: 149/250 [60%] deaths with perioperative chemotherapy v 170/253 [67%] deaths with surgery alone; HR for death 0.75, 95% CI 0.60 to 0.93, P = 0.009). The sixth subsequent RCT (40 people with locally advanced gastric tumours (T3 and T4) without distant metastases) compared surgery plus intra-arterial chemotherapy versus surgery alone. The RCT found no significant difference between groups in mean survival (50 months 95% CI 42 to 81 months with surgery plus intra-arterial chemotherapy v 62 months, 95% CI 34 to 66 months with surgery alone, P = 0.9).

Harms

Adjuvant chemotherapy versus surgery alone:

The fist review gave no information on harmsand the second review reported mild toxicity but gave no further details.

Two RCTs included in the review reported toxicity (mainly nausea and vomiting) in 53% of people. Serious toxicity was usually because of cardiac or cumulative haematological problems; treatment-related mortality was 1–2%. One subsequent RCTs reported no significant difference in postoperative complications with adjuvant chemotherapy. One subsequent RCT reported 4/93 (4%) chemotherapy-related deaths. Most people in the RCT stopped or reduced chemotherapy, because of adverse effects. The RCT of gastro-oesophageal cancers reported no clinically significant increase in the incidence of grade 3 or grade 4 toxic effects.The sixth subsequent RCT reported minor toxicity in three people receiving surgery plus intra-arterial chemotherapy (no further data reported).

Comment

Two RCTs included in the systematic review may have been duplicate versions of the same RCT. Preoperative superselective intra-arterial chemotherapy may not be available outside of specialist centres.

Substantive changes

Adjuvant chemotherapy One systematic review and one subsequent RCT added comparing adjuvant chemotherapy versus surgery alone. The review found that adjuvant chemotherapy reduced mortality compared with surgery, but the subsequent RCT found no significant difference in mean survival rates between adjuvant chemotherapy and surgery alone. Categorisation unchanged (Likely to be beneficial).


Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group